Background Cardiovascular-kidney-metabolic (CKM) syndrome is a novel staging construct that reflects the pathophysiological interplay between these individual conditions. The long-term trends in the prevalence of CKM syndrome in the US have not been well characterized. Methods This serial cross-sectional study used data from the National Health and Nutrition Examination Survey (1999-2018) to define CKM stages from 0 (no risk factors) to 4 (clinical CVD). Participants younger than 20 years, pregnant patients, and those with missing mortality data and NHANES fasting subsample weights were excluded. We calculated the age- and sex-adjusted prevalence of each stage and its trends. Survey-weighted Cox regression was used to estimate the mortality risk with each stage. Stata 17.0 was used for all analyses. Results The prevalence of CKM syndrome at each stage was as follows: stage 0, 11.9%; stage 1, 24.9%; stage 2, 49.1%; stage 3, 4.6%; and stage 4, 9.5%. The prevalence of CKM stages 0 and 4 decreased between 1999-2018, but that of CKM stages 1 and 3 increased. The risk of all-cause and CVD mortality showed a graded increase from stage 1 to 4 compared to stage 0 (HRs for all-cause death in stage 4 = 2.87, 95% CI: 1.98-4.17, and CVD death = 4.68, 95% CI: 1.95-11.26). Conclusions Almost 90% of US adults have stage 1 or higher CKM syndrome, which is associated with an increased risk of mortality. The increasing trend in stage prevalence further underscores the need for multidisciplinary interventions to control risk factors and prevent progression.